Influenza virus is a global health threat that is responsible for over 300,000 deaths annually. The virus evades immune recognition by engaging in a combination of accelerated antigenic drift, domain reassortment, genetic recombination, and glycosylation based masking of its surface glycoproteins. This rapid mutation capability of the virus is particularly exacerbated in the context of the growing threat from the present H1N1 ‘swine flu’ pandemic as well as the alarming worldwide spate in recent infections with highly pathogenic avian H5N1 ‘bird flu’ influenza strains. (Khanna et al., Journal of Biosciences, 33(4):475, 2008, Soundararajan et al., Nature Biotechnology 27:510, 2009). Furthermore, two of the major flu pandemics of the last century originated from avian flu viruses that changed their genetic makeup to allow for human infection.
There is a need for the development of effective anti-influenza prophylactics and therapeutics. Furthermore, given the high degree of unpredictability in evolution of these influenza viruses, there is a particular need for the development of cross-strain effective (e.g., “universal” or “broad spectrum”) anti-influenza prophylactics and therapeutics. Such effective anti-influenza agents, and particularly such universal or broad spectrum anti-influenza agents could replace or augment vaccines designed to target specific ‘seasonal’ viral strains in circulation (Ekiert et al., Science, 324(5924):246, 2009 and Sui et al., Nat Struct Mol. Biol. 16(3):265, 2009). Alternatively or additionally, there is a need for the development of effective anit-influenza prophylactis or therapeutics that can replace or augment current anti-viral therapy. The importance of such agents is highlighted by the emerging drug resistance to current antivirals Tamiflu/Relenza (NA-inhibitors) and Amantadine/Rimantadine (MP-2 inhibitors) (Collins et al., Nature 453:1258, Stouffer et al., Nature, 451:596, 2008, Pielak et al., Proc. Natl. Acad. Sci. USA, 106:7379, 2009). For instance, over 98% and 100% of H1N1 strains in the 2011/2012 flu season are resistant to Tamiflu and the adamantane derivatives (Amantadine/Rimantadine), respectively.